This application details a two-part, five-year research career development program in mucosal immunity and mucosal vaccinology. The program will be conducted under the mentorship of Dr. Stephen B. Calderwood, Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA. The candidate is trained in Infectious Diseases and Tropical Medicine and has the long-term career goals of gaining expertise in vaccinology with special emphasis on mucosal immunity. The program will include sessions of instruction in laboratory techniques and courses in microbiology, molecular genetics and vaccinology at Harvard University. The research component of the program will focus on the development and evaluation of live, attenuated Vibrio cholerae to act as a delivery vehicle for heterologous antigens presented at mucosal surfaces. Three specific aims will be addressed: optimization of the in vivo expression of heterologous antigens by live, attenuated V. cholerae utilizing both constitutive and in vivo-regulated promoters; evaluation of the potential of attenuated, detoxified heat-labile enterotoxin of Escherichia coli (LT), expressed by V. cholerae vector strains, to act as an immunoadjuvant; and evaluation of the ability of live, attenuated V. cholerae vector strains to deliver heterologous antigens derived from specific microbial pathogens to mucosal surfaces. The applicant's progress and research will be overseen by the mentor and by an advisory committee of scientists at the Harvard Medical School and Massachusetts General Hospital. The program will allow the candidate to obtain the skills, knowledge and experience to become an independent biomedical researcher in mucosal immunity and mucosal vaccinology.